The supplies of liquid blood and blood components are currently limited by storage systems used in conventional blood storage practices. Using current systems, stored blood expires after a period of about 42 days of refrigerated storage at a temperature above freezing (i.e., 4° C.) as packed blood cell preparations. For example, in 2007, more than 45 million units of red blood cells (RBCs) were collected and stored globally (15.6 million in the US). During refrigerated storage, RBCs become progressively damaged by complicated biological changes collectively referred to as “storage lesions.” When transfused within the current 6-week limit, stored RBCs have lower quality as well as potential toxicity, which can be manifested as side effects of transfusion therapy. Among the observed storage lesions are altered biochemical and physical parameters associated with stored red blood cells. Examples of these alterations include in vitro measured parameters such as reduced metabolite levels (adenosine triphosphate (ATP) and 2,3 diphosphoglycerate (2,3-DPG)), increased levels of cell-free iron, hemolysis, increased levels of microparticles, reduced surface area, echinocytosis, phosphatidylserine exposure, and reduced deformability. Expired blood cannot be used and must be discarded because it may harm the ultimate recipient. These reasons and others limit the amount of readily available high quality blood needed for transfusions.
When stored conventionally, stored blood undergoes a steady deterioration which is associated with various storage lesions including, among others, hemolysis, hemoglobin degradation, and reduced ATP and 2,3-DPG concentrations. When transfused into a patient, the effects of the steady deterioration during storage manifest, for example, as a reduction in the 24-hour in vivo recovery. Because of these and other medical sequelae of transfusion of stored blood, a variety of approaches have been developed to minimize the effects of storage on blood and to improve medical outcomes. See, for example, Zimring et al., “Established and theoretical factors to consider in assessing the red cell storage lesion” in Blood, 125:2185-90 (2015).
A number of approaches have been developed aimed at minimizing storage lesions and improving transfusion outcomes. One approach has been the development of additive solutions included during storage. Examples of this approach include U.S. Pat. No. 4,769,318 to Hamasaki et al. and U.S. Pat. No. 4,880,786 to Sasakawa et al. which are directed to additive solutions for blood preservation and activation. For example, Rejuvesol (available from Citra Lab LLC, Braintree, Mass.) is added to blood after cold storage (i.e., 4° C.) just prior to transfusion or prior to freezing (i.e., at −80° C. with glycerol) for extended storage. U.S. Pat. No. 6,447,987 to Hess et al. is directed to additive solutions for the refrigerated storage of human red blood cells. An alternative approach is to freeze the blood and prevent the development of storage lesions. Storage of frozen blood is known in the art, but such frozen blood has limitations. U.S. Pat. No. 6,413,713 to Serebrennikov is directed to a method of storing blood at temperatures below 0° C. See Chaplin et al., “Blood Cells for Transfusion,” Blood, 59: 1118-20 (1982), and Valeri et al., “The survival, function, and hemolysis of human RBCs stored at 4 degrees C. in additive solution (AS-1, AS-3, or AS-5) for 42 days and then biochemically modified, frozen, thawed, washed, and stored at 4 degrees C. in sodium chloride and glucose solution for 24 hours,” Transfusion, 40:1341-5 (2000). Another approach relates to the containers for blood storage as provided by U.S. Pat. No. 4,837,047 to Sato et al.
One approach that has proven successful in improving blood quality and extending its utility is through the depletion of oxygen and storage under anaerobic conditions. U.S. Pat. No. 5,624,794 to Bitensky et al., U.S. Pat. No. 6,162,396 to Bitensky et al., and U.S. Pat. No. 5,476,764 to Bitensky are directed to the storage of red blood cells under oxygen-depleted conditions. U.S. Pat. No. 5,789,151 to Bitensky et al. is directed to blood storage additive solutions. Among the benefits of storing blood under oxygen depleted conditions are improved levels of ATP and 2,3-DPG, reduced hemolysis. Storing blood under oxygen depleted conditions can also result in reduced microparticle levels, reductions in the loss of deformability, reduced lipid and protein oxidation and higher post transfusion survival when compared to blood stored under conventional conditions.
U.S. Pat. No. 6,162,396 to Bitensky et al. (the '396 patent) discloses anaerobic storage bags for blood storage that comprise an oxygen impermeable outer layer, a red blood cell (RBC) compatible inner layer that is permeable to oxygen having an oxygen scrubber placed between the inner and outer layers. The blood storage device further comprises at least two ports for conventional sterile connections for introducing whole blood or RBCs into the device. The '396 patent generally discloses oxygen impermeable outer layers but does not provide guidance regarding specific types of materials or suitable construction methods. Similarly, the '396 patent discloses inner blood compatible layers generally but does not provide guidance regarding appropriate materials and construction methods. Similarly, the '396 patent does not provide guidance on tubing materials and methods to gain access to the inner blood bag and contents while maintaining a reduced oxygen environment.
During the course of research to develop an ASB for use in blood collection and blood banking operations, it was observed that additional considerations were necessary. First, in preparing oxygen impermeable outer layers, it was observed that not all of the materials identified as suitable in the '396 patent could be used in practicable devices. Specifically, it was observed that certain aluminum foil laminated membranes became compromised when creased, wrinkled or folded. More problematic, is that upon introduction of blood into such bags, the increase in volume directly led to the formation of such integrity compromising creases. To avoid this complication, appropriate materials having sufficient flexibility are required. Alternatively, ASBs having suitable expansion features that provide for the accommodation of the blood are required.
Also during the course of development, it was observed that the bag integrity needed to be maintained at the various ports to prevent ingress of oxygen prior to use and also during storage. Another source of oxygen ingress was observed at seams and joints wherein wider seals provided for both decreasing oxygen leakage and preventing outer and inner bag failure. It was further observed that the standard PVC tubing used in blood banking operations had significant permeability to oxygen and incompatibility with methods to create an oxygen impermeable seal where it passed through the outer oxygen impermeable barrier. Even further, conventional blood collection kits require transfer tubing ranging in length from about greater than or equal to 200 mm as well as collection tubing having a length greater than or equal to 800 mm that are also potential sources of oxygen introgression. See ISO 3826-1:2013. Thus, blood collection kits for anaerobic storage of blood must account for this source of oxygen that can diminish the capacity of an oxygen sorbent placed in the ASB and significantly reduce the shelf life of the resulting bags.
Therefore, there is a need for improved anaerobic blood storage bags that provide for extended shelf life a blood collection kit including such bags. There is also a need for improved anaerobic storage bags that can provide for the ingression of oxygen through the tubing associated with blood collection kits. Finally, there is a need to identify suitable materials that can accommodate routine handling of blood storage bags that do not compromise the integrity of the oxygen barrier.
Finally, the integration of oxygen indicators into improved anaerobic blood storage bags provides additional levels of quality control that helps inform the users of possible oxygen ingress that are large enough to compromise the ability to the storage bag to maintain the depleted blood in an oxygen depleted condition.